Cathepsin D expression has been assessed by immunohistochemistry in 108 cases of Non-Small Cell Lung Cancer (NSCLC) and its expression has been related to conventional prognostic factors such as tumor size, tumor grade, histotype and nodal involvement. The cancer cells in 41.6% of the tumors showed a granular, cytoplasmic cathepsin D (C-D) positivity. Moreover, some benign macrofage-like stromal cells expressed similar positivity. The C-D immunoreactivity was significantly associated with non-squamous histotype, small size, less advanced and more differentiated cancers. Additionally, in non-squamous tumors we observed a higher significant expression in early-staged (T1-2, NO) than in more advanced neoplasias. No significant associations were found between C-D and Ki-67, PCNA immunoreactivity, DNA ploidy or flow cytometric S-phase data. These findings suggest that NSCLCs also express C-D but, as previously reported for breast cancers, the immunohistochemical C-D expression has a good prognostic significance unlike the results obtained by cytosolic evaluation.